The hypothalamus acting through the pituitary is important for organismal adaptation to homeostatic challenges. Dysfunction in these systems impairs health, increases addictive behaviors and is a common cause of relapse. Elucidating the molecular cellular mechanisms is therefore critical for understanding, preventing, or treating a variety of associated disorders including substance abuse. The hypothalamic corticotrophin-releasing factor (CRF) and pituitary pro-opiomelanocortin (POMC) neurons are evolutionarily conserved across vertebrates. They control organismal responses to aversive stimuli through regulating circulating neuropeptides and glucocorticoids. However, it remains poorly understood how CRF and POMC neurons are regulated by both external environment and internal neural states. Neuromodulatory systems are involved, but because of the pleiotropic action of most neuromodulatory systems, it has been difficult to understand their role in CRF-POMC regulation in cell type- and gene-specific manners. Dopamine (DA) is a classical neurotransmitter that is best known for its role in signaling reward. Dopamine also plays a critical but poorly understood role in hypothalamic-pituitary regulation in a variety of species including humans, dogs, rats, mice, and fish. Recently, we have uncovered that dopamine (DA) regulates CRF-POMC function in larval zebrafish through both D1 and D2 receptors. This study will employ the transparent and highly accessible larval zebrafish system and advanced molecular genetic technologies to understand the mechanisms by which dopamine regulates CRF-POMC function. This study will unveil new molecular and cellular mechanisms on how DA neurons interact with CRF and POMC neurons to regulate their function. The findings will provide new insights into the development function and evolution of these important neural systems in the context of organismal survival and wellbeing. Equally importantly, this proposal will establish broadly applicable tools for genetically dissecting neuromodulatory systems in complex behaviors.